TAP dysfunction in dendritic cells enables non-canonical cross-presentation for T cell priming

Classic MHC-I presentation relies on shuttling cytosolic peptides into the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP). Viruses disable TAP to block MHC-I presentation and evade cytotoxic CD8(+) T cells. Priming CD8(+) T cells against these viruses is thought to rely solely on cross-presentation by uninfected TAP-functional dendritic cells (DCs). We found that protective CD8(+) T cells could be mobilized during viral infection even when TAP was absent in all hematopoietic cells. TAP blockade depleted the endosomal recycling compartment (ERC) of MHC-I and as such impaired Toll-like receptor-regulated cross-presentation. Instead, MHC-I accumulated in ER-Golgi intermediate compartments (ERGIC), sequestered away from Toll-like receptor control, and coopted ER-SNARE Sec22b-mediated vesicular traffic to intersect with internalized antigen and rescue cross-presentation. Thus, when classic MHC-I presentation and ERC-dependent cross-presentation are impaired in DCs, cell-autonomous non-canonical cross-presentation relying on ERGIC-derived MHC-I counters TAP dysfunction to nevertheless mediate CD8(+) T cell priming.